PhD Projects
MRC Funded PhD Projects

We offer two types of 4-year MRC Prize Studentships. We encourage students to take the programme with two 4.5 month rotation projects followed by the main PhD project. Students will gain considerable research experience before starting their PhD, and exposure to two different labs can be very helpful in deciding which PhD project and which lab to work in. In the second 4 year programme students just choose one lab to work in for their PhD.

There is no deadline for MRC funded PhD applications

The following PIs are offering PhDs through the School of Sciences PhD program
Miratul Muqit

Details of other PhD Projects offered by PIs in the Unit can be found here.
  1. Clinical PhD Fellowships in cancer or neurodegeneration

 

Dario Alessi - Understanding how disruptions in signalling pathways cause human disease


My laboratory focuses on unravelling the roles of components that regulate protein phosphorylation and ubiquitylation pathways emerging from the analysis of human disease. The aim of our work is to discover how these pathways are organised, how they recognise signals, how the signal moves down the pathway to elicit physiological responses and to comprehend what goes wrong in human disease. We hope that these findings will enable us to play the engineer in devising new strategies to treat disease. Wherever possible, we will work closely with pharmaceutical companies, as well as chemical biologists, to help with the development of tool compounds that specifically inhibit the signalling components with which we are working. In combination with genetic approaches, these tool compounds will be very powerful in helping us to decipher the physiological roles of signalling pathways and in validating to what extent inhibiting these networks effectively suppresses disease.

Possible projects include
1. Understanding the important role that LRRK2 protein kinases plays in Parkinson’s disease. This project aims to build on recent progress that our laboratory has made (PMID:27474410 and 26824392). It is aimed a deciphering how LRRK2 is regulated and functions and how mutations in this enzyme cause Parkinson’s disease.

2. Defining the important role that SGK3 kinase plays in cancer and mediating resistance to PI3K pathway therapies (PMID: 27481935 and 25177796). The goal of this project will be to identify the critical substrates for the SGK3 kinase and study how they regulate cancer relevant biology.

3. We would like to initiate a new project to study the phosphorylation of hydroxylated proline residues of protein in biology. The aim would be to discover proteins that are phosphorylated on hydroxylated proline and then identify the kinases and phosphatases that act on these.

 

 

Greg Findlay - Erk5-Dependent Mechanisms Which Determine Embryonic Stem Cell Identity

Pluripotent Embryonic Stem Cells (ESCs) have the capacity to differentiate into all specialized cell types, including brain, heart, lung, liver and pancreas. ESC identity is tightly controlled by protein kinase signaling, which our lab seeks to exploit towards the application of ESCs in tissue regeneration. In a small molecule kinase inhibitor screen, we uncovered a critical function for the Erk5 kinase in controlling ESC pluripotency. Using inhibitor engineering and CRISPR/Cas9 genome editing, we show that Erk5 modulates transition between “naïve” and “primed” pluripotent ESC states. Excitingly, we also find that Erk5 restrains cardiac specific gene expression and differentiation of ESCs to functional cardiomyocytes.
This project aims to apply cutting-edge technologies to unravel the molecular mechanisms by which Erk5 controls ESC identity. The successful applicant will use phosphoproteomics to identify Erk5 substrates, and total cell proteomics and RNA-SEQ transcriptomics to explore the wider role of Erk5 in regulating protein-coding and non-coding gene expression. This knowledge will then be exploited to promote cellular reprogramming and differentiation of cardiac tissue from pluripotent cells.

 

 

Ian Ganley - Finding the eat-me signals

The Ganley lab is interested in unravelling the molecular mechanism of autophagy (which literally translates from the Greek meaning to eat oneself). Autophagy functions to clear the cell of potentially damaging agents, such as protein aggregates or faulty mitochondria, as well as acting as a recycling station to supply essential building blocks during periods of starvation. The autophagy field is a rapidly growing area of research, one of the reasons being that it is dysregulated in many diseases and therefore its modulation could lead to novel therapies. To enable this, we first need to understand the machinery involved. A project is available to decipher the signals that lead to the specific autophagy of mitochondria (termed mitophagy), a process that has been linked to Parkinson’s disease and cancer. Following up on recently published work (Allen et al., EMBO Rep, 2013; McWilliams et al., J Cell Biol, 2016), the project will utilise state-of-the-art microscopy, protein biochemistry and high-throughput screening to identify phosphorylation and ubiquitylation events involved in capturing mitochondria for degradation..

References
Allen, G. F., Toth, R., James, J. and Ganley, I. G. (2013). Loss of iron triggers PINK1/Parkin-independent mitophagy. EMBO Rep 14, pp. 1127-1135
McWilliams, T. G., Prescott, A. R., Allen, G. F., Tamjar, J., Munson, M. J., Thomson, C., Muqit, M. M. and Ganley, I. G (2016). mito-QC illuminates mitophagy and mitochondrial architecture in vivo. J Cell Biol 214, pp. 333-345

 

 

Yogesh Kulathu - Regulation of protein degradation by the ubiquitin system

Protein degradation is a fundamental process in cells that is important for timely elimination of damaged proteins. This process relies on modification of proteins with ubiquitin, a signal to target destruction of modified proteins via the proteasome. Failure to eliminate damaged/misfolded proteins is an underlying cause of age-related diseases such as Alzheimer’s and Parkinson’s disease. Excitingly, we have recently discovered a new family of proteins that regulate protein degradation signals. The aim of this project is to decipher how protein homeostasis is regulated by these newly identified players. In your PhD, you will employ a range of techniques including biochemical approaches, state-of-the-art ubiquitin proteomics, mouse models and CRISPR/Cas9 genome-editing methods to elucidate new layers of control in protein degradation, research that will advance our understanding of neurodegenerative diseases.

 

 

Karim Labib - How to copy a chromosome

Chromosome duplication is one of the most complex processes in eukaryotic cell biology, and is extremely important for our understanding of human cancer. Our cells produce a single near-perfect copy of the genetic blueprint in each cell cycle, and the duplicated sister chromatids must also inherit the same epigenetic landscape as their parents, and be held together by cohesion until mitosis. For all these reasons, the chromosome replication machinery is highly complex, and is regulated extensively by post-translational modifications. These are exciting times to study the process of chromosome duplication, the mechanism and regulation of which are highly conserved in all eukaryotic species. It is now possible to envisage projects that range from in vitro reconstitution of complex cellular processes, via cutting edge genetics and cell biology in yeast and worm embryos, to genome editing in mammalian cells by CRISPR-Cas9.

Project 1: The role of ubiquitylation in replication termination
We showed that disassembly of the replication machinery is controlled in yeast by a ubiquitin ligase and an ATPase called Cdc48 (Maric et al, Science, 2014, Maculins et al, Curr. Biol., 2015). The mechanisms and regulation remain to be elucidated, and we are now also searching for factors that regulate this process in higher eukaryotes.

Project 2: Epigenetic inheritance during chromosome replication
How do cells ensure that the epigenetic landscape is inherited faithfully when the chromosomes are unwound and duplicated? We showed that the replication machinery plays an active role in this process (Foltman et al, Cell Reports, 2013), but many fundamental questions remain unanswered. In parallel to unravelling the basic mechanisms in yeast, we aim to explore the impact of this regulation for development in higher eukaryotes, using models ranging from worm early embryos to mouse embryonic stem cells.



 

 

John Rouse - Recognizing and repairing chromosome damage

DNA is highly chemically reactive; there are many agents that occur normally inside cells that react with DNA in a way that could change the sequence and/or structure of the genome, with potentially catastrophic consequences. In addition to their potential mutagenicity, DNA damage can block important processes such as DNA replication, which can potentially prevent cell proliferation. So it’s important that DNA damage is repaired rapidly to prevent mutations, rearrangements or changes in chromosome number from occurring.

We are interested in how cells detect, signal and repair DNA damage and how they deal with blocks to DNA replication. In the past years we have discovered a range of completely new proteins in mammalian cells that are instrumental for repair of DNA damage and broken replication forks. Some of these – such as SLX4 – are mutated in debilitating human diseases. We are interested in figuring out the modes of action of these proteins and their relevance to disease, and in discovering more new players in DNA repair. Many important chemotherapeutic agents act by inducing DNA damage and/or DNA replication stress and we are interested in finding ways of making these therapies more effective and in preventing resistance. Furthermore we are involved in identifying new anti-cancer drug targets in the DNA repair arena.

We are particularly interested in DNA inter–strand crosslinks (ICLs). These are formed when bifunctional agents covalently link the two strands in a double helix. ICLs are toxic lesions that prevent strand separation necessary for transcription and DNA replication. ICLs are caused by endogenous metabolites, and the major route for ICL repair appears to be initiated when DNA replisomes collide with ICLs. The repair of ICLs involves multiple DNA repair pathways, but how they are removed and DNA replication re-started is unclear. Failure to repaie ICLs in humans causes the inherited disease Fanconi anaemia characterised by developmental abnormalities, bone marrow failure and cancer predisposition.

Project 1: How does protein ubiquitylation promote ICL repair?
We have set up new assays to identify new DNA repair genes and this project involves using these assays to screen for new regulators of DNA repair. We have already identified some new candidates that need to be characterised in detail

Project 2: A “ synthetic rescue” approach to treating diseases caused by defective DNA repair
Women with a germline mutation in the BRCA1 tumour suppressor gene have a very high chance of developing in breast or ovarian cancers. Cells from patients with BRCA1 mutations show defects in a mode of DNA repair referred to as homologous recombinbation, and as a result they show a high degree of genome stability and problems with proliferation. A number of groups found that deleting the 53BP1 DNA repair gene is able to reverse many aspects of the phenotype associated with BRCA1 mutations. In animal models 53BP1 deletion greatly reduced the incidence of tumours associated with BRCA1 mutations. The logic behind this story is that when BRCA1 is absent, 53BP1 initiates an inappropriate mode of DNA repair that BRCA1 would normally prevent. The project on offer aims to use a synthetic rescue screening strategy to find ways of rescuing the DNA repair defects seen in Fanconi anaemia and other debilitating diseases caused by DNA repair.

 

 

Gopal Sapkota -Dissecting the roles of the FAM83 family of proteins in cells and disease through exploitation and development of cutting-edge technologies

Some recent discoveries in our lab have established key roles for relatively uncharacterised PAWS1/FAM83G, and the FAM83 family of proteins to which PAWS1 belongs, in tissue homeostasis, development and disease. One of the major focus of the lab is to understand how PAWS1 and the FAM83 family function and are regulated in cells and how their malfunction manifests in human diseases. The prospective PhD projects in this area include: 1) Dissecting the molecular roles and regulation of PAWS1 in development and signal transduction. 2) Assigning the biochemical and molecular role(s) for the domain of unknown function, DUF1669, which links the members of the uncharacterised FAM83 family of proteins. Prospective PhD candidates will exploit cutting-edge technologies, including CRISPR/Cas9 genome editing, mass spectrometry, ChIP and RNA sequencing as well as transgenic mouse models, to establish the physiological roles and regulation of PAWS1 and other members of the FAM83 family. Advancing new technologies to address fundamental biological questions is another area of our interest. With this in mind, the third prospective PhD project aims to develop and test applications of the Affinity-directed PROtein Missile (AdPROM) system, which combines CRISPR/Cas9 and nanobodies to target endogenous proteins, for research into protein function and drug discovery.

 

 

Satpal Virdee - Activity-based Profiling of E3 Ligases

E3 ligases impart the specificity in ubiquitin attachment and are also dysregulated in a number of diseases. As a result, E3s have become attractive therapeutic targets. PhD projects are available in the Virdee lab working on the application and further development of revolutionary new chemical probe technology. We have devised activity-based probes which can be used to profile the activity of ~50 E3 ligases in a single experiment1. E3 activity is typically regulated by posttranslational mechanisms and is difficult, if not impossible, to measure by conventional proteomic and transcriptomic approaches. Our probes provide a unique opportunity to study the regulation of E3 activity in a number of disease-relevant contexts such as cancer, autoimmunity and neurodegeneration2.

We have PhD projects that will apply our technology for the identification of aberrantly activated E3s that are present in disease-relevant cellular systems thereby gaining biological insight and potentially uncovering novel therapeutic targets. We also have projects that will involve the development of efficient platforms for screening and selectivity profiling for small molecule modulators of E3 ligases2.

References

1. Pao, K.-C. et al. Probes of ubiquitin E3 ligases enable systematic dissection of parkin activation. Nature Chemical Biology 12, 324–331 (2016).
2. Niphakis, M. J. & Cravatt, B. F. Enzyme inhibitor discovery by activity-based protein profiling. Annu Rev Biochem 83, 341–377 (2014).

 

 

Helen Walden - Understanding ubiquitination in Parkinson’s Disease

The Walden lab is focussed on uncovering the mechanisms of protein ubiquitination in health and disease. Dysfunction of several genes and proteins in the ubiquitin proteasome pathway (UPS) contribute to the pathogenesis of Parkinson’s Disease. Using a combination of structural biology and biochemistry, PhD projects are available to study how proteins are targeted for ubiquitination by proteins required for neuronal health, and what goes wrong in the disease contexts.